METABOLIC ACIDOSIS AND THE DISSOCIATION CURVE OF HEMOGLOBIN DURING EXTRACORPOREAL CIRCULATION

Jb~i Thoracic and Cardiovascular Surgery

VOLUME 38 NOVEMBER 1959 NUMBER 5

Original Communications METABOLIC ACIDOSIS AND THE DISSOCIATION CURVE OF HEMOGLOBIN DURING EXTRACORPOREAL CIRCULATION George J. Magovern, M.D. (by invitation), Robert S. Cartwright, M.D.* (by invitation) , John F. Neville, Jr., MD.** (by invitation), and Edward M. Kent , MD. , Pittsburgh, Pa.

T

value of hemoglobin as an oxygen carrier lies in the fact that its affinity for oxygen is so balanced that, in the lungs, hemoglobin becomes 95 to 96 per cent oxygenated, while in the tissues and the capillaries it ra n give up as much of th e oxygen as demanded. The relationship between oxygen tension and the degr ee of saturation of hemoglobin has been studied in blood and in solutions of hemoglobin by Huffner, Bohr, and others. The effect of alkalinity was first noted by Bohr, Hasselbalch, and Krogh' who observed that increasing carbon dioxide tension decreased the amount of oxygen bound by hemoglobin. Barcroft": 3 showed that the degree of oxygenation, although dependent chiefly on the oxygen pressure, also increased with the alkalinity and the electrolyte content of the blood. They subsequently showed that the effect of carbon dioxide was due to its acidity and that the addition of other acids to the blood had a similar influenc e. Fig. 1 depicts the S-shaped curve of oxyhemoglobin dissociation and shows the relationship between oxygen tension, oxygen saturation, and varying pH. It will be noted that, as the blood becomes more acid , hemoglobin combines with less oxygen and, as the blood becomes more H E PHYSIOLOGIC

From the Department of Thoracic S\lrgery and the Sur-gfcal R es earch Laboratory. Universtty of Prttsburgh, School of Med icine, and the Presbyterian Hospital and Allegheny General Hospital . Pit.tsburgh, Pa. Read at the Thirty-ninth Annual Meeting of The A m e r ica n Association for Thoracic ~\Irgery at Los Angeles. Calif.. A pril 21-23. 1959. • Present address: Lovelace Clinic and Foundation. A lb u que r q ue , N. ::.1<1. "Present add ress : State U n i ve rsit y of New York. Upstate Di vision, Syrac\lse. N. Y,

561

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alkaline, the opposite is noted. Conversely, the amount of oxygen which is released to the tissues is greater at a reduced pH than it is at an alkaline pH. It is this behavior which enables oxygen to dissociate from the blood as it reaches the tissues, taking up in its place carbon dioxide. The changes in oxyhemoglobin dissociation effected by changes in the pH is known as the Bohr effect. The purpose of this study was to determine to what advantage this physiologic reaction may be applied during extracorporeal circulation. It was based on clinical observations in our own series of approximately 100 open-heart operations. In 12 instances when the arterial pH was reduced, we believed a clinical improvement and a gross color change were brought about by the addition of sodium bicarbonate to the blood during bypass.

l1ilHmetef''' oXYl!en tension Fig. i.-Relationship between oxygen tension and oxygen saturation of human blood at varying pH. Curves calculated by Richards and Strauss (Ref. 14).

METHOD

A. Experimental Procedure.-Twenty-five dogs were anesthetized with Pentothal sodium, 30 mg. per kilogram of body weight. Utilizing a multiple disk Kay-Cross oxygenator and 95 per cent oxygen and 5 per cent carbon dioxide, the animals were placed on total cardiopulmonary bypass. This was done through a right thoracotomy which was performed under aseptic technique. Venous drainage was enacted into the oxygenator by gravity after catheters were placed in the superior and inferior vena cava via the right atrial appendage. The arterial return was through the right femoral artery. The left femoral artery was cannulated with a No. 190 polyethylene catheter for continuous monitoring of the arterial pressure. This catheter was threaded into the central aorta and the pressure was determined with an aneroid manometer. A similar catheter was placed into the inferior vena cava through the saphenous vein and

\'01. 38. !'io. ; Xovernber, 19.;9

METABOLIC ACIDOSIS

563

connected to a saline manometer for continuous monitoring of the venous pressure. After tapes were placed around the superior and inferior vena cava, the catheters were inserted and total cardiopulmonary bypass was begun. The animals were perfused according to the amount of venous return, maintaining a venous pressure of 0 to 1 em. of water. The animals varied in weight from 12 to 22.5 Kg. and were perfused at flow rates of 26 to 87 c.c. per kilogram a minute. After complete bypass was initiated and satisfactory flow and oxygenation were achieved, hypoxia was produced by reducing the revolutions of the disks from 120 to approximately 60 r.p.m. This caused inadequate surface area exposure, resulting in reduction of the partial pressure of oxygen and undersaturation of the blood. Particular emphasis was placed on the avoidance of changes in the blood level in the oxygenator and flow rates once the experiment was begun. With the development of hypoxia, monitoring of the pH was carried out and, as acidosis occurred due to the anoxia, the pH was noted to fall. At a reduced pH, which averaged approximately 7.25, samples of blood at the venous inlet and the arterial outlet of the oxygenator were taken for measurement of oxygen and, carbon dioxide content. The pH at the arterial end of the oxygenator was simultaneously recorded at this time. Correction of the reduced pH was then attempted by the addition of alkali or the creation of respiratory alkalosis. The alkali added was either sodium bicarbonate, 44.6 mEq. per 50 C.c. of solution or 1 M sodium-r-lactate, 1 mEq. per cubic centimeter of solution. The production of respiratory alkalosis was achieved by changing the gas mixture from 95 per cent oxygen and 5 per cent carbon dioxide to 100 per cent oxygen, thereby allowing carbon dioxide to escape from the blood. E. Analytical Methods.-The following determinations were performed on the blood samples: (1) plasma pH, (2) total carbon dioxide content, and (3) total oxygen content. Total oxygen capacity was determined from a sample taken from the oxygenator at the completion of the experiment so that complete mixing of the patient and donor blood was achieved, thereby giving an over-all hematocrit. Two of the experiments were analyzed for sodium, potassium, chloride. The pH determinations were done on whole blood at a constant temperature of 36° C. in a Beckman model G pH meter, accuracy plus or minus 0.05 pH units. Total carbon dioxide, total oxygen content, and oxygen capacity were determined according to the method of Van Slyke and Neill." Sodium and potassium determinations were carried out on a Coleman flame photometer. Chloride was determined according to the method of Sendroy and his associates." C. Calculations.-The pC0 2 • and base bicarbonate were calculated from the measured pH and the total plasma carbon dioxide, using the HendersonHasselbalch equation with pK' equal to 6.10. The plasma carbon dioxide was calculated from the whole blood carbon dioxide content." The per cent of oxygen saturation was calculated by dividing the total oxygen content by the total oxygen capacity and multiplying by 100. The oxygen tension of the blood was determined from the pH and arterial saturation." • Partial pressure of carbon dioxide expressed in millimeters of mercury.

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MAGOVERN, CARTWRIGHT, NEVILLE, KENT

RESULTS

Seven experiments were discarded because of changes in the blood in the oxygenator which could have influenced the oxygen saturation. In the remaining 18 experiments, reduction in the pH was brought about in all cases. Correction of the reduced pH was accomplished in 11 experiments bv the addition of sodium bicarbonate, by the creation of respiratory alkalosis in 2, and by the addition of molar sodium-r-lactate in 1. In 4 other animals, the addition of sodium lactate failed to bring about elevation in the pH. TABT,E I.

EXPER.

ARTERIAL

NO.

pH

1 2 3 4. 5 6 7 9 12 15 17 18 19 20

7.27 7.18 7.25 7.27 7.23 7.35 7.28 7.26 7.21 7.14 7.28 7.24 7.25 7.28 7.25

Averages

I

E~'~'ECT OF CORRECTED

IKTTIAL ART.

vzx.

(MM.

SA~'.

SA~'.

48 75 70 56 43 41 58 100 55 43 66 55 10;{ 85 64

I (%) I (%) 74.0 8g.5 88.6 81.0 67.2 70.8 83.5 99.5 72.0 58.0 88.0 79.8 98.0 94.3 81.7

CALCl:LATED

OBSERVED

po, ng )

pIF

-

55.0

-

56.0

-

17,4

-

49.3 23.0 49.3 35.3 63.5 61.0 45.5

AR-

~'~;RIAL

pH

7,42 7.30 7.60 7.70 7.52 7.59 7.35 7.45 7.26 7.38 7.54 7.46 7.61 7.40 7,47

\

po, (MM.

ng) 48 80 62 32 35 :14 55 46 35 30 56 46 38 56 47

ART. SAT.

VEl'. SAT.

80.8 92.8 96.0 76.5 72.8 75.6 84.7 82.0 60.0 55.0 92.0 83.6 81.7 87.9 80.1

60.8

I (%) I (%) -

53.0 -

16.3 -

17.g 10.7 49.2 83.6 43.5 5'1.6 ·1:l.:1

ARTERIAL

pH

7.27 7.18 7.2;'3 7.27 7.23 7.35 7.28 7.26 7.21 7.14 7.2g 7.24 7.2.j 7.2R 7.~3

I

po, (MM.

Hg) 48 80 62 :12 35 in 55 46 35 30 56 -16 38 56 47

ART.

SA'r.

I (0/1- ) 74 ~)O

81 50 34 42 80 70 52 48 81 69 50 80 65

'This table depicts the degree of oxygen saturation of the blood w h lch was obtatned when the oxygen tension was reduced and the pH simultaneously elevated by the addition of alkali or the creation of respiratory alkalosis. The calculated results are theoretical saturations which would have been expected if the p H were not corrected as the oxygen tension was de-

creased.

Table I depicts the pIl, partial pressure of oxygen, and the arterial and venous saturation before and after the correction of the pH. In Column 3 of Table I are the calculated oxygen saturations of the arterial samples which would have been present at the reduced P0 2 , · if the pH had not been corrected. It is observed (Table I) that in the 14 experiments in which the pH was corrected that the observed average oxygen saturation was 15 per cent greater than the calculated arterial saturation despite the reduction in the oxygen saturation and partial pressure. Table II shows the arteriovenous difference which was obtained in 9 of the experiments before and after the correction of the pH. It is noted that the elevation of the p H, although allowing the blood to pick up additional oxygen during its passage through the oxygenator, did not inhibit the release of this oxygen to the tissues since the arteriovenous difference is greater, despite the shift of the oxyhemoglobin dissociation curve toward the alkaline side. This apparent discrepancy in the action of the oxyhemoglobin dissociation curve is explained below. 'Partial pressure of oxygen in millimeters of mercury.

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20

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10

0

ui

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I

I

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40

30

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T IME

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70

80

9 0

;

.Lr.; uio 120

( mi D . )

F i/<. 2.-Cll n ·e s ho wi ng the c han ge In the avera ge pH a nd oxyg en s aturation during the onset o f hypoxia . a n d a f ter the add ition o f sodiu m bi carbonate. T ABLE

IT.

A RTERIOVE NOUS D IFF EREN CE " HIGH p H

LOW pH EXl'ER. NO.

:? 4 I

12 15 Ii

18

HI

20 A ver ages

A·V Diff ere nce

VEN .

AR'r. SAT .

S A~'.

ART. S AT.

VEN . SAT .

(% )

(% )

(%)

(%)

88.5 81.0 83.5 72.0 58.0 88.8 79.8 98.0 94.3 H2.7

55.0 56.0 17.4 49.3 23.0 49 .3 35.3 63.5 61.0 45.5

92.8 79.5 84.7 60.0 55.0 92.0 83.6 81.7 87.9 80.5

60.8 53.0 16 .3 17.8 10.7 49.2 46.1 43.5 54.6 39.1

37.2

41.4

' T he a r t e r iove no u s di ffe re n ce in 9 anima ls before a n d afte r the correction of the pH of the bl ood , This shows that the correc t ton of the pH toward the n ormal or alkaline range p r ev ent ox ygen di ssociation In the caplIJaries. not did

7.25 7.25 7.23 7.20 7.28 7.17 7.14 7.25 7.13

pn 7.27 7.00

[,OW

I

88.6 70.4 6-1.-.) 68.8 83.5 95.1 88.7 97.4 90.8

74.0 85.5

(%)

ART. 0,

I

8.4 :18.9 43.8 :16.0 28.9

-

-

-

40.5 (% Sat.) 29.9

ART. CO., (VOl,. %)

I

7.2 51.7 66.0 50.8 43.3

-

-

:1:,.8

-

pco, (MM. ng)

I

4.25 17.9 22.0 1-I.~., 14.1

-

l·U

-

anco, (mM/L.)

lIT.

7.60 7.70 7.52 7.59 7.78 7.45 7.38 7.61 7.40

r.ao

pn

7.42

HIGH

I 96.0 79.5 72.8 75.6 86.3 82.2 55.5 98.2 87.9

(%) 80.8 95.8

ART. 0,

I

SOlHFlII BICARBOKATE··

a4.0 75.1 40.2 54.7 45.3

-

85.1 (% Sat.) 65.5

-

ART. co, (VOL. %)

I

13.5 58.5 ;{6.7 46.5 40.3

-

-

il7.0

-

19.4 a9.3 20.8 27.6 24.1

-

-

35.0

-

-

-

Hg)

I (mM/L. naco, )

poo, (MM.

156.1 156.1 89.2 111.5 89.2 133.8 44.6 44.6 44.6

133.8 624.4

(mzq.)

xanco,

17

25 30 :,5 9 19

.)" _iJ

20 75

63 55

TIME (DlF. MIN.)

I

'The results in eleven of the experiments in which sodium bicarbonate was used to correct the acidosis. The last two columns show the number: of milliequivalents given and the time in minutes between the lowest and highest pH determtnattons.

il 4 5 6 7 9 15 19 20

~

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NO.

EX PER.

'l'ABLE

-:..;,

tt:1

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0"0 0"0

ME'l'ABOLIC ACIDOSIS

Vol. 38,1\0.5 ~o\'emher, 19S9

567

Table III and Fig. 2 illustrate the changes in those animals which received sodium bicarbonate. The pC0 2 and BHC0 3 determined in 6 of these experiments shows that the addition in the total carbon dioxide content of the blood is reflected as an increase in the BHC0 3 • IV.

TABLE

EXPER. NO.

LOW pH

11 12 13 14 16

7.48 7.21 7.32 7.29 7.28

I

ART. 0,

SODIUM LACTATK'-

pn 7.24 7.36 7.29 7.21 7.14

(%)

HIGH

94.02 72.95 94.11 77.13 93.70

I

ART. 0,

(%) 96.66 60.26 72.21 63.10 88.68

TOTAL LACTATE

(c.c.)

I (DIF.TIME I MIN.)

120 80 200 160 160

34 35 38 50 25

0, & CO,

(%) & 5 & 5 & 5 & 5 & 5

95 95 95 95 95

'The results in 5 animals given 1 M sodtum-r-Iactate solution. Note the failure to change the pH of the blood. and the continued fall in oxygen saturation. The time differential is the time between the addition of lactate and the taking of the sample for pH and oxygen saturation. Column 3 is labeled "high pH" and is the pH after the addition of sodium lactate. Note the failure to raise the pH in four of the five experiments.

Table IV depicts the results in those. animals who received sodium lactate 150 to 200 c.c, of a molar solution. Foul' of the 5 animals failed to show any change in the pH of the blood. In 2 experiments, a change in the pH was induced by the development of respiratory alkalosis. This is illustrated in Table V and shows that respiratory alkalosis can induce a marked change in the pl I. No striking change in the arteriovenous difference was noted so that the amount of oxygen delivered to the tissues was apparently not increased. TABLE

pH

Experiment 17 95% 0, and 5% CO, 100% 0,

Experiment 18 95% 0, and 5% CO, 100% 0,

V.

RESPIRATORY ALKALOSIS*

ART. 0, SAT. (VOL. %)

I

7.21 7.28

15.69 15.20

7.40 7.54

15.24 15.44

7.24

14.23

7.46

14.90

I

ART. co, (VOL. %)

ART. pco, (MM. Hg)

ART. BHC0 3 (mM/L.)

vnx. 0, (VOL. %)

52.01 55.94

52.3 51.0

21.7 23.5

8.95

23.8

:1~.O

19.8 19.8

8.21

52.0

22.5

6.29

2;3.1

17.3

8.21

46.4;3 45.54 Capacity 16.88

51.89 40.24 Capacity 17.84

H.22

'The effects of respiratory alkalosis produced in 2 animals by removing carbon dioxIde from the oxygenating mixture. Note the marked reduction in pCO,.

DISCUSSIOK

The design of the experiment was to reproduce the clinical situation resulting in inadequate oxygenation of the patient during cardiopulmonary bypass. This has been shown to result in a gradual production of metabolic acidosis." Clinically this can occur if the flow rate of the patient exceeds the oxygenating capacity of the oxygenator or by the opposite situation of inadequate venous return because of insufficient gravity, faulty placement of the caval cannulae,

568

MAGOVERN, CARTWRIGHT, NEVILLE, KENT

J. Thoracic and Cardiovas. Surg.

or blood loss. This will result in inadequate arterial output and, despite adequate oxygenation of the blood as it passes through the oxygenator, the total amount of oxygen delivered to the patient will not supply his demand. The situation to a lesser degree may also be encountered if the donor blood is improperly stored and glycolysis markedly reduces the pH of the blood. This latter situation may be particularly compounded in those patients with cyanotic heart disease in whom it ha~ been shown that some degree of metabolic acidosis is present." These patients frequently, during preparation for bypass, will have a reduced cardiac output with hypotension and additional acidosis may occur before actual bypass is begnn. Considerable desaturation of the tissues may be present and, if a high flow rate cannot be achieved to correct this during bypass, further acidosis and desaturation of the blood occurs, resulting in a markedly desaturated venous return which mav overtax the efficiency of the oxygenator. The net result in these situations is a fall of oxygen tension, inadequate oxygen saturation, tissue hypoxia, and metabolic acidosis. The body has two main lines of defense to prevent further hypoxia. 'I'hev are the favorable dissociation of oxyhemoglobin at low oxygen tissue pressures and the reinforcement of this effect by the p I I gradient between the arterial and capillary blood favoring further release. Because of the A-shaped curve of oxyhemoglobin dissociation it was necessary to illustrate these effects in our experiments to reduce the oxygen tension of the blood to approximately 30 to 50 mm. Hg. As is illustrated in Fig. 1, at higher oxygen saturations, changes in pH would not well illustrate the Bohr effect. As the disk speed was reduced, however, it was impossible to achieve a constant oxygen tension since the animal was continuously depleting the oxygen content of the arterial return and, during the time that the bicarbonate, lactate, or respiratory alkalosis was effected, further reduction in the tension took place. We, therefore, determined the oxygen tension at the p H and oxygen saturation of the arterial blood before and after the correction of the pH and calculated what the saturation of the arterial blood would have been at this reduced oxygen tension if the pH had not been corrected. This is shown in Table 1. In those instances in which the arterial saturation was within normal range and in which oxygen tension was onlv mildly reduced when the pH was concomitantly reduced the addition 0 f sodium bicarbonate actually raised the oxvgcn saturation, illustrating the true Bohr effect, that is, an increase in the oxygenation of the blood by the addition of alkali at a constant oxygen tension. In the remaining instances, although t ho correction of the pH did not raise the oxygen saturation of the blood, when COIllpared to the initial sample, this could not be expected because of the continuing drop in oxygen tension. It did, however, prevent a further loss of saturation since, despite the further reduction in oxygen tension, an almost similar average arterial oxygen saturation was achieved. The fundamental question to be answered, however, was the method by which the arterialized blood achieved greater saturation. 'Vas this at the expense of the tissues? Did the elevation of the pH in effect prevent release to the tissues so that the arteriovenous differenees before and after the correction of the p H were essentiallv similar:

569

METABOLIC ACIDOSIS

Vol. 38, No . .I November, 19.19

Table II shows the arteriovenous differences and, on the average, the tissues were able to extract more oxygen after the correction of the pH than before. It will be noted that at the higher oxygen saturations the change in arteriovenous difference was insignificant despite the correction of the pH. However, at the reduced saturations there were greater arteriovenous differences. This can be explained from the dissociation curve. At the higher saturations, pH has little effect on dissociation, but at reduced tensions it becomes quite significant. For example, Fig. 3 is a line chart showing the amount of oxygen bound by the hemoglobin of the blood of Dr. A. V. Bock at varying oxygen tensions and serum pH. At 30 mm. of oxygen tension, increasing the pH from 7.25 to 7.70 JpH of ftserum

\Jork

Rest

Blood of AVBock.

at !'est and at

\./0('11.

o

Fig. 3.-Line chart showing the amounts of oxygen bound by hemoglobin of the blood of Dr. A. V. Bock at different serum pH and oxygen tension (Ref. 7).

increases oxygenation 35 per cent. The converse of this is also illustrated in Fig. 3 where the slight lowering of the blood pH when it receives carbon dioxide from the tissues assists in releasing additional oxygen. Thus, from the above chart, it is evident that if Dr. Bock at work had maintained an arterial pH in the capillaries, a drop to 32 mm. of oxygen tension in the capillaries would have left 56 pel' cent of the venous hemoglobin in the oxygenated state instead of the observed 50 pel' cent. This represents 13 pel' cent of the total oxygen released from the blood that is due to the slight lowering' of the pH. The effect of oxygen tension in vivo is illustrated in Fig. 1. At p H 7.4, the first 30 mm. of oxygen tension grosses 56 per cent oxygenation of the hemoglobin in contrast to an increase of 30 mm. of tension at the top of the seale changing

570

MAGOVERN, CARTWRIGHT, NEVILLE, KENT

J. Thoracic and Cardiovas. Surg.

the oxygenation only 6 per cent. When unusual demands in the tissue require oxygen, the last 30 mm. of oxygen tension causes a yield of more than half the arterial oxygen content. It is evident that at high oxygen tensions the addition of alkali to the blood will have little physiologic advantage but in situations as may occur during extracorporeal circulation in which the arterial saturation is reduced and tissue hypoxia is present, the correction of the pH toward the alkaline side will allow greater uptake of oxygen in the oxygenator, but will not affect the tissue pH to the extent that it will not be able to extract this additional oxygen from the blood as it reaches the tissue. We believe from our results that the correction of the pH allowed the blood to combine with more oxygen during its passage through the oxygenator increasing the total amount of oxygen available. However, on reaching the tissues the reduced oxygen tension and the additional tissue acidosis more than offset the increased oxygen affinity brought about by the change to the alkaline side, and therefore more oxygen was actually released to the tissues. In addition, by preventing further desaturation of the venous return additional strain on the oxygenator was prevented. The cycle of events which could be brought about by further venous desaturation, that is, reduced arterial saturation, reduced tissue oxygen tension, further extraction of oxygen, and a further reduction in venous saturation, was ameliorated. One of the practices which is carried out during cardiac surgery is to hyperventilate the patient prior to bypass, creating a respiratory alkalosis and an elevated pH. This change in pH should favorably effect the oxyhemoglobin dissociation curve if severe hypoxia is present as illustrated above. However, recent work'" 11. 1" has shown that hyperventilation is accompanied by increased production of lactic acid. This is predominantly an intracellular acidosis and is accompanied by an exchange of sodium for hydrogen ion. Elkinton and his eo-workers 11 have shown that in acute respiratory acid-base disturbances transfer of intracellular cation occurs probably as the result of the changes of extracellular pH. No positive or negative load of fixed cation is imposed on the body as in the case of metabolic disturbances. Ninety per cent or more of the change in effective extracellular bicarbonate was extrarenal!" and was related to changes in hydrogen ion uptake or release by buffer protein in the blood and by ionic transfer into or out of the cellular fluid in the body. Their results in respiratory alkalosis indicate that part of the cellular buffering consisted in release of hydrogen 'ion with the release of an undetermined ion, probably lactate, since an increase of extra cellula r lactic acid has been specifically reported to occur with respiratory alkalosis.": 1:1 Thus, it would appear that deliberate introduction of respiratory alkalosis before bypass would result in increased lactic acid formation and be actually more detrimental to the patient during extracorporeal circulation. Table II illustrates the failure of sodium lactate to produce any change in the pH of the blood in 4 of the 5 animals when it was added during extracorporeal circulation. The lactate was administered rapidly and the animal received approximately 150 to 200 e.c, of molar sodium lactate in a half-hour period. Although the blood sodium following lactate administration became

\"01. 38,

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Xovember ,

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19_~9

~IETABOLIC

ACIDOSIS

571

elevated, obviously sufficient time had not elapsed for the metabolism by the liver to release bicarbonate. During extracorporeal circulation to effect changes in pH, sodium lactate is apparently not rapidly enough metabolized to effect these changes. 'With the present improvements in pump-oxygenators and the greater experience gained from their application, oxygenation of blood does not now appear to be a significant problem. However, occasionally situations do arise in which, because of blood loss or lack of blood reserve in the system, a compromise on the flow rate may become necessary. Under these circumstances, increasing metabolic acidosis will result and the addition of sodium bicarbonate to counteract the release of lactic aeid in this situation appears to be indicated. During the past year we have continuously monitored pH of the blood during bypass and if the pH falls below 7.3 sodium bicarbonate, 4 mEq. per kilogram of body weight is given directly into the oxygenator. This has been given over a 10minute period on 12 different patients and it has been noted in these cases to effect correction of the pH and at times a gross improvement in the oxygenation of the blood. In these cases, we have not observed any adverse effects and found that postoperative acidosis, as illustrated by urine pH and blood pH determinations which would have been expected in these cases, has not been a problem. SUlIIMARY

Eighteen mongrel dogs were placed on extracorporeal bypass and metabolic acidosis was deliberately introduced by underoxygenation of the blood. 'When the pH of the blood was lowered, blood samples were taken for arterial and venous oxygen saturations. The pH was then corrected in 14 of these animals. It was done by the addition of sodium bicarbonate in ] 1 with the creation of respiratory alkalosis in 2 and the addition of sodium laetate in 1; the addition of sodium lactate in 4 other animals failed to affect any change in the pH. Oxygen tension was determined from the pH and the saturation of the blood at the corrected pH and compared to the calculated oxygen saturation of the blood at the same oxygen tension if the pH were not corrected. The data illustrated that the Bohr effect, particularly at reduced oxygen tensions, raised the oxygen saturation of the blood during its passage through the oxygenator approximately 15 per cent. Despite the correction of the pH, a greater arterial venous difference was noted, thereby effecting greater transport of oxygen to the tissues. The effect of sodium lactate was found in 4 out of 5 animals to be ineffective in creating a pH change. This is explained by the inadequate time elapsed between the addition of lactate and the pH determinations to allow for sufficient metabolism of the lactate. Respiratory alkalosis was effective in 2 animals in elevating the pH and the physiologic effects of respiratory alkalosis were briefly discussed. The clinical application of the results of this experiment was briefly presented. REFEREXCES

1. Bohr, C., Hasselbalch, K., and Krogh, A.: Ueber einen in biologischer Beziehung wicht.igen Einfluss den die Kohlensaurespannung des Blutes auf dessen Sauerstoffbin dung ubt, Skand. Arch. Physiol. 16: 402, H107.

572

~IAGOVERN,

CARTWRIGHT, NEVILLE, KEN'l'

J. Thoracic and Cardiovas. Surg.

2. Barcroft, .J.: The Respiratory Function of the Blood, Cambridge, England, 1914, University Press. 3. Barcroft, J.; The Respiratory Function of the Blood. II. Hemoglobin, Cambridge, 192H, University Press. 4. Van Slyke, D. D., and Neill, J. M.: The Determination of Gases in Blood and Other Solutions by Vacuum Extraction and Manometric Measurement. I., J. BioI. Chern. 61: 523, 1924. 5. Fister, H ..J.: Manual of Standardized Procedures for Spectrophotometric Chemistry, New York, ]950, Standard Scientific Supply Corp. (i. Van Slyke, D. D., and Sen droy, J., .Ir.: Line Charts for Graphic Calculations by the Henderson-Hasselbalch Equation, and for Calculating- Plasma Carbon Dioxide Contents Frolll Whole Blood Content, .J. BioI. Chern. 79: 7H], ]92H. 7. Bock, A. V., Dill, D. B., Hurxthal, L. M., Lawrence, .r, S., Coolidg-e, T. C., Da iley, M. E., and Henderson, L. .J.: Blood as a Physicochemical System. V. 'I'he Composition and Respiratcrv Exchanges of Normal Human Blood During- Work. .1. BioI. Chem. 73: 749, 1927. S. Litwin, M. S., Panico, F. H., Iiubini, C., Harken, D. F., ancl Moore, F. R.: Acidosis and Lacticacidemia in Extracorporeal Circulation, Ann. Rmg. 149: IHS, 1959. 9. Morse, M., and Cassells, D. E.: Arterial Blood Gases and Acid Base Balance in Cyanotic Congenital Heart Disease, J. Clin. Invest. 132: 837, 1!l53. lI1. Barker, E. S., Singer, R. B., Elkinton, J. R., ancl Clark, J. K.: Renal Response in Man to Acute Experimental Respiratory Alkalosis and Acidosis, .J. Clin. Invest. 36: 5]5, 1957. 11. El k in ton, .J. R., Singer, R. B., Barker, E. S., and Clark, J. K.: Effect in Man of Acute Experimental Respiratory Alkalosis and Acidosis on Ionic Transfer in Total Body Fluids, J. Clin, Invest. 34: 1671, 1955. 12. Papadopoulos, C. N., and Keats, A. S.: The Metabolic Acidosis of Hyperventilation Produced by Controlled Respiration, Anesthesiology 20: 156, 1959. 1:1. Carrver, H. M.: Tissues Anoxia Resulting From Respiratory Alkalosis, Proc. Staff Meet. Mayo Clin. 22: 456, 1947. 14. Richards, D. W., .Ir., and Strauss, M. L.: Oxyhemoglobin Dissociation Curves of Whole Blood in Anemia, .J. Clin. Invest. 4: 105, 1926. (For Discussion; see page 6.18.)